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Natural history of neuromyelitis optica

EMA Regulatory Workshop on Clinical Trials Designs in Neuromyelitis Optica

and Spectrum Disorders London, 10 October 2014

Friedemann Paul

NeuroCure Clinical Research Center Clinical and Experimental Multiple Sclerosis Research Center

Department of Neurology Charité University Medicine Berlin, Berlin, Germany

friedemann.paul@charite.de

Previous data on NMO cohorts (selection)

Country N Reference

UK 12 O‘Riordan et al. J Neurol Neurosurg Psychiatry 1996

USA 71/80 Wingerchuk et al. Neurology 1999; Wingerchuk and Weinshenker Neurology 2003

USA 96 Wingerchuk et al. Neurology 2006

Italy 46 Ghezzi et al. J Neurol 2004

France 13 De Seze et al. J Neurol Sci 2002

France 125 Collongues et al. Neurology 2010

Japan 35 Takahashi et al. Brain 2007

Mexico 34 Rivera et al. J Neurol 2008

Germany 175 Jarius et al. J Neuroinflammation 2012

UK 106 Kitley et al. Brain 2012

Differences in ethnicity

NEMOS cohort

Caucasian 175/175 (100%)

Non-Caucasian 0/175 (0%) Collongues et al. Neurology 2010

Wingerchuk et al. Neurology 2006

Neurology 1999

Neurology 1999

• 60 % of relapsing patients were functionally blind in at least one eye • 52% of relapsing patients had permanent monoplegia or paraplegia

Neurology 2003

Neurology 2007

Caveats when assessing natural history in NMO

Retrospective cohorts New diagnostic criteria (Wingerchuk et al. 2006, IPND 2014/2015) Increased awareness for the disease owing to broad availability of AQP4

testing Subsequently, lower number of misdiagnoses? NEMOS cohort: in 43% initial diagnosis of MS (54% before 2005, 20% after

2005) Assumption: patients are diagnosed earlier and thus treated earlier Increased awareness for detrimental of uneffective MS therapies in NMO

(IFN-beta, NAT, FTY) How does treatment influence disease course? Benign NMO?

Neurology 2006

JNNP 2009

• 96 patients from Cuba and French West Indies • 70% with severe visual loss in one eye, 48% in both • Median times to DSS 3, 6 and 8 in RNMO were 1, 8 and 22 years • 25% died after a disease duration of 11 years

Jarius et al. J Neuroinflammation 2012

Jarius et al. J Neuroinflammation 2012

Jarius et al. J Neuroinflammation 2012

Jarius et al. J Neuroinflammation 2012

Jarius et al. J Neuroinflammation 2012

- 4 disease related deaths after disease duration of 6, 116, 158, 284 months - median time to EDSS 6-6.5 appr. 5 years

Brain 2012

Arch Neurol 2011

„Natural history“?????

spinal surgery with biopsy postoperative EDSS 8 (vs. 4) postoperative CSF leakage patient remained wheelchair bound

MSJ 2013

MSJ 2013

Summary

Most studies are consistent regarding the devastating disease course in many patients

Accrual of irreversible neurological disability ist almost exclusively attack-related, a progressive course is rare

Mortality seems to have decreased, presumably related to earlier diagnosis and treatment

Effective immunosuppression is likely to positively modify disease course Although a subset of patients may have mild disease, the concept of „benign

NMO“ remains elusive and should not lead to therapeutic nihilism Prevention of further attacks should be the major goal of long-term treatment

and in clinical trials

Thanks to all NEMOS collaborators

Bayreuth: U Hofstadt-van Oy, R Reuss Berlin: L Harms, F Paul, C Pfueller, K Ruprecht Bochum: K Hellwig, R Linker Dortmund: S Niehaus Düsseldorf: O Aktas, HP Hartung, M Ringelstein Frankfurt: C Mayer, U Ziemann Görlitz: K Guthke Göttingen: W Brück, I Metz Halle: F Hoffmann, C Zentner Hannover: M Stangel, C Trebst Hamburg: S Schippling Heidelberg: S Jarius, B Wildemann Leipzig: B Ettrich, F then Bergh, F Moeller, E Thomae München: A Berthele, B Hemmer, T Kümpfel Münster: M Marziniak Neubrandenburg: T Böttcher Plauen: C Wilke Regensburg: I Kleiter Rostock: A Winkelmann, UK Zettl Sigmaringen: O Neuhaus Stralsund: JP Sieb, C Veauthier Teupitz: J Faiss, P Kern Tübingen: A Melms Ulm: J Brettschneider, F Lauda, H Tumani Würzburg: C Geis, C Kleinschnitz

special thanks to Sven Jarius and Orhan Aktas